Lung cancer is the leading cause of cancer deaths globally [1]. Non-small-cell lung cancer (NSCLC) accounts for over 80% of all the histological classified lung cancer cases, and patients are often diagnosed at the advanced stages of the disease, therefore the prognosis of lung cancer remains poor [2]. With the advanced development of DNA sequencing technology, the therapeutic strategy of NSCLC has been modified towards to personalized therapy. Some specific driver genetic mutations have been identified in NSCLC, such as EGFR [3, 4], EML4-ALK fusion gene [5] and ROS fusion gene [6], which directs the development of molecular-targeted drug discovery to target theses mutations. Among those mutations, EGFR mutation is the most frequently observed gene mutation in Eastern Oriental population, especially in subgroup of patients who are non-smoker, female, clinically diagnosed with Adenocarcinoma and early onset. The common activating mutation of EGFR is a substitution mutation of EGFRL858R, which makes EGFR constitutively activated even without EGF stimulation, resulting in downstream activation of anti-apoptotic signaling. Gefitinib, which is a tyrosine kinase inhibitor (TKI), can specifically inhibit EGFR as well as its downstream survival signaling pathway [7]. However, despite the initial significant responses to Gefitinib treatment, like other chemotherapeutic agents, patients acquire resistance to Gefitinib ultimately, and the median time to disease progression is just about 12 months [8]. The most common reasons of Gefitinib resistance is the presence of additional EGFR mutation (EGFRL858R+T790M), which accounts for over 49% of all the resistance cases. The additional T790M mutation will provide steric hindrance to TKI due to the bulkiness of Methionine (M), thus the overall pharmaceutical effect of Gefitinib is weakened. Therefore, it is an urgent need to identify EGFR crosstalk pathways and to discover more effective agents as new candidate drugs for Gefitinib-resistant NSCLC patients.
Sanguinarine, a benzophenanthridine alkaloid, can be isolated from Chinese medicinal herb Macleaya cordata or from North American herb sanguinaria canadensis. Macleaya cordata injection has been utilized as clinical application for treating inflammation. As a major constituent, the pharmacological effects of sanguinarine have been widely studied in many fields for a long time, for example, as anti-microbe [9, 10], anti-inflammation [11, 12] and anti-oxidation [13, 14], but not in the field of NSCLC, especially on Gefitinib-resistant NSCLC. It has acquired the FDA approval as an antibacterial or antiplaque agent in toothpastes in 2003 [15]. Using the drug discovery method as disclosed in the present invention demonstrates the cytotoxic potency of sanguinarine and other chemical agent in treating and selectively targeting Gefitinib-resistant NSCLC. In the present invention, methods for treating and selectively targeting a specific Gefitinib-resistant NSCLC which harbors an additional mutation by using sanguinarine and at least one chemical agent will also be disclosed.